Form of S-omeprazole

ABSTRACT

The present invention relates to a novel form of the (−)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1 H -benzimidazole, i.e. S-omeprazole. More specifically, it relates to a novel form of the magnesium salt of the S-enantiomer of omeprazole trihydrate. The present invention also relates to processes for preparing such a form of the magnesium salt of S-omeprazole and pharmaceutical compositions containing it. Furthermore, the present invention also relates to new intermediates used in the process.

This application is a 371 of PCT/SE98/00974, May 5, 1998 now WO 9854171Dec. 3, 1998.

FIELD OF THE INVENTION

The present invention relates to a novel form of the (−)-enantiomer of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole,i.e. S-omeprazole. More specifically, it relates to a novel form of themagnesium salt of the S-enantiomer of omeprazole trihydrate. The presentinvention also relates to processes for preparing such a form of themagnesium salt of S-omeprazole and pharmaceutical compositionscontaining it. Furthermore, the present invention also relates tointermediates used in the process, and their preparation.

BACKGROUND OF THE INVENTION AND PRIOR ART

The compound5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,having the generic name omeprazole, and therapeutically acceptable saltsthereof, are described in EP 5129. The specific alkaline salts ofomeprazole are disclosed in EP 124 495. Omeprazole is a proton pumpinhibitor, i.e. effective in inhibiting gastric acid secretion, and isuseful as an antiulcer agent. In a more general sense, omeprazole may beused for prevention and treatment of gastric-acid related diseases inmammals and especially in man.

Omeprazole is a sulfoxide and a chiral compound, wherein the sulfur atombeing the stereogenic center. Thus, omeprazole is a racemic mixture ofits two single enantiomers, the R and S-enantiomer of omeprazole, hereinreferred to as R-omeprazole and S-omeprazole. The absoluteconfigurations of the enantiomers of omeprazole have been determined byan X-ray study of an N-alkylated derivative of the (+)-enantiomer innon-salt form. The (+)-enantiomer of the non-salt form and the(−)-enantiomer of the non-salt form were found to have R and Sconfiguration, respectively, and the (+)-enantiomer of the magnesiumsalt and the (−)-enantiomer of the magnesium salt were also found tohave R and S configuration, respectively. The conditions for the opticalrotation measurement for each of these enantiomers are described in WO94/27988.

Certain salts of single enantiomers of omeprazole and their preparationare disclosed in WO 94/27988. These compounds have improvedpharmacokinetic and metabolic properties which will give an improvedtherapeutic profile such as a lower degree of interindividual variation.

WO 96/02535 discloses a process for the preparation of the singleenantiomers of omeprazole and salts thereof, and WO 96/01623 discloses asuitable tableted dosage forms of for instance magnesium salts of R- andS-omeprazole.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a X-ray powder diffractogram of the magnesium salt ofS-omeprazole trihydrate prepared according to the present invention.

FIG. 2 shows a X-ray powder diffractogram of the potassium salt ofS-omeprazole prepared and used in the present application (See examples2 and 3)

FIG. 3 shows a X-ray powder diffractogram of a magnesium salt ofS-omeprazole dihyclrate prepared and used in the present application(See example 5)

FIG. 4 shows a X-ray powder diffractogram of a magnesium salt ofS-omeprazole dihyclrate which is a polymorph of the dihydrate shown inFIG. 3 (See Example 6). This magnesium salt of S-omeprazole dihydratehas been prepared and can be used in the preparation of the magnesiumsalt of S-omeprazole trihydrate according to the present invention.

FIG. 5 shows X-ray powder diffractogram of the magnesium salt ofS-omeprazole prepared according to example A in WO 96/01623.

DESCRIPTION OF THE INVENTION

It has surprisingly been found that the magnesium salt of S-omeprazoleoccurs in a number of structurally different forms. It is an object ofthe present invention to provide a substantially pure magnesium salt ofS-omeprazole trihydrate, hereinafter referred to as the compound of theinvention. This trihydrate can be obtained as a well defined compound.The present invention also provides a process to obtain and a method ofdifferentiating the magnesium salt of S-omeprazole trihydrate from otherforms of magnesium salts of S-omeprazole.

The compound of the invention is advantageous because it is more stablethan the corresponding magnesium salt compounds in prior art and istherefore easier to handle and store. The compound of the invention isalso easier to characterize because it exists in a well defined state.Additionally, the compound of the invention is easier to synthesize in areproducible manner and thereby easier to handle in a full scaleproduction.

The magnesium salt of S-omeprazole trihydrate obtained according to thepresent invention is substantially free from magnesium salts ofR-omeprazole. The magnesium salt of S-omeprazole trihydrate obtainedaccording to the present invention is also substantially free from otherforms of magnesium salts of S-omeprazole, such as the correspondingmagnesium salt compounds described in prior art, and dihydrates used inthe preparation of the trihydrate compound according to the presentinvention.

The compound of the invention is characterized by the positions andintensities of the major peaks in the X-ray powder diffractogram, butmay also be characterized by conventional FT-IR spectroscopy. Thesecharacteristics are not exhibited by any other form of magnesium salt ofS-omeprazole and accordingly, the magnesium salt of S-omeprazoletrihydrate is easily distinguishable from any other crystal form of themagnesium salt of S-omeprazole disclosed in prior art. The compound ofthe invention is characterized by being highly crystalline, i.e. havinga higher crystallinity than any other form of magnesium salt ofS-omeprazole disclosed in the prior art. With the expression “any otherform” is meant anhydrates, hydrates, solvates, and polymorphs oramorphous forms thereof disclosed in the prior art. Examples of anyother forms of magnesium salt of S-omeprazole includes, but are notlimited to, anhydrates, monohydrates, dihydrates, sesquihydrates,trihydrates, alcoholates, such as methanolates and ethanolates, andpolymorphs or amorphous forms thereof.

The compound of the invention may also be characterized by its unitcell.

In a further aspect, the present invention provides processes for thepreparation of the magnesium salt of S-omeprazole trihydrate whichcomprises;

a) treating a magnesium salt of S-omeprazole of any form, for exampleprepared according to procedures known in the art such as Example A inWO 96/01623 which is incorporated herein by reference, with water at asuitable temperature for a suitable time. By a suitable temperature ismeant a temperature which induces the transformation of startingmaterial to product without decomposing any of these compounds. Examplesof such suitable temperatures include, but are not limited to, roomtemperature and above. By a suitable time is meant a time that resultsin high conversion of the starting material into product without causingany decomposition of either compounds, i.e. results in a good yield.This suitable time will vary depending on the temperature used in a waywell known to people in the art. The higher the temperature, the shortertime is needed to give the desired conversion. The amount of water isnot crucial and will depend on the process conditions used. Themagnesium salt of S-omeprazole trihydrate is thereafter separated fromthe aqueous slurry, for example by filtration or centrifugation andthereafter dried to constant weight; or

b) oxidizing5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole,with an oxidizing agent and a chiral titanium complex, optionally in thepresence of a base. The oxidation is carried out in an organic solvent,for example toluene or dichlromethane.

The crude product is converted to the corresponding potassium salt bytreatment with a potassium source, such as methanolic potassiumhydroxide or methanolic potassium methylate, followed by isolation ofthe formed salt.

The resulting potassium salt of S-omeprazole is thereafter converted tothe corresponding magnesium salt by treatment with a magnesium source,such as magnesium sulfate in a lower alcohol, such as methanol. Thesolution is optionally filtered and the precipitation is initialized byaddition of a non-solvent such as acetone. The product is filtered offand optionally washed with water and further processed as is describedin a) above. Alternatively, the potassium salt may be treated with amagnesium source, such as magnesium sulfate in water, and isolation ofthe magnesium salt of S-omeprazole trihydrate, or any other conventionaltechnique for transforming a potassium salt to the correspondingmagnesium salt can be used and is within the scope of the presentinvention.

Yet a further aspect of the present invention is to provide a suitableintermediate used in the preparation of the compound of the invention,as well as a process for its preparation. The potassium salt ofS-omeprazole is found to be such a suitable intermediate. The potassiumsalt of S-omeprazole may also be used as an active component of apharmaceutical formulation to be used in the treatment ofgastrointestinal diseases.

The compound of the invention, i.e. the magnesium salt of S-omeprazoletrihydrate, prepared according to the present invention may be analyzedby XRPD, a technique which is known per se.

The amount of water in the magnesium salt of S-omeprazole trihydrate isdetermined by thermogravimetric analysis, a technique which is known perse.

The compound of the invention is effective as a gastric acid secretioninhibitor, and is useful as an antiulcer agent. In a more general sense,it can be used for prevention and treatment of gastric-acid relatedconditions in mammals and especially in man, including e.g. refluxesophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer.Furthermore, it may be used for treatment of other gastrointestinaldisorders where gastric acid inhibitory effect is desirable e.g. inpatients on NSAID therapy, in patients with Non Ulcer Dyspepsia, inpatients with symptomatic gastro-esophageal reflux disease, and inpatients with gastrinomas. The compound of the invention may also beused in patients in intensive care situations, in patients with acuteupper gastrointestinal bleeding, pre- and postoperatively to preventaspiration of gastric acid and to prevent and treat stress ulceration.Further, the compound of the invention may be useful in the treatment ofpsoriasis as well as in the treatment of Helicobacter infections anddiseases related to these. The compound of the invention may also beused for treatment of inflammatory conditions in mammals, including man.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of the magnesium salt of S-omeprazoletrihydrate, according to the invention. For example, peroral or parentalformulations and the like may be employed. Dosage forms includecapsules, tablets, dispersions, suspensions and the like.

It is further provided a pharmaceutical composition comprising themagnesium salt of S-omeprazole trihydrate according to the invention, asactive ingredient, in association with a pharmaceutically acceptablecarrier, diluent or excipient and optionally other therapeuticingredients. Compositions comprising other therapeutic ingredients areespecially of interest in the treatment of Helicobacter infections. Theinvention also provides the use of the magnesium salt of S-omeprazoletrihydrate of the invention in the manufacture of a medicament for usein the treatment of a gastric-acid related condition and a method oftreating a gastric-acid related condition which method comprisesadministering to a subject suffering from said condition atherapeutically effective amount of the magnesium salt of S-omeprazoletrihydrate according to the invention.

The compositions of the invention include compositions suitable forperoral or parental administration. The most preferred route is the oralroute. The compositions may be conveniently presented in unit dosageforms, and prepared by any methods known in the art of pharmacy.

In the practice of the invention, the most suitable route ofadministration as well as the magnitude of a therapeutic dose of themagnesium salt of S-omeprazole trihydrate according to the invention inany given case will depend on the nature and severity of the disease tobe treated. The dose, and dose frequency, may also vary according to theage, body weight, and response of the individual patient. Specialrequirements may be needed for patients having Zollinger-Ellisonsyndrome, such as a need for higher doses than the average patient.Children and patients with liver diseases generally will benefit fromdoses that are somewhat lower than the average. Thus, in some conditionsit may be necessary to use doses outside the ranges stated below, forexample long term treatments may request lower dosage. Such higher andlower doses are within the scope of the present invention. Such dailydoses may vary between 5 mg to 300 mg.

In general, a suitable oral dosage form of the compound of the inventionmay cover a dose range from 5 mg to 300 mg total daily dose,administered in one single dose or equally divided doses. A preferreddosage range is from 10 mg to 80 mg.

The compound of the invention may be combined as the active component inintimate admixture with a pharmaceutical carrier according toconventional techniques, such as the oral formulations described in WO96/01623 and EP 247 983, the disclosures of which are herebyincorporated as a whole by reference.

Combination preparations comprising the magnesium salt of S-omeprazoletrihydrate and other active ingredients may also be used. Examples ofsuch active ingredients include, but are not limited to anti-bacterialcompounds, non-steroidal anti-inflammatory agents, antacid agents,alginates and prokinetic agents.

The examples which follow will further illustrate the preparation of thecompound of the invention, according to different process routes andincluding new intermediates. These examples are not intended to limitthe scope of the invention as defined hereinabove or as claimed below.

EXAMPLES Example 1

S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt trihydrate

Water (157 kg) was added to the wet crystals of the magnesium salt ofS-omeprazole, prepared according to Example 4, below. The mixture washeated to 38° C. with stirring and left for 3 hours. The crystals werefiltered off and dried in vacuo. Yield: 31.6 kg

X-ray powder diffraction analysis was performed on a sample of thecrystals prepared above according to standard methods, which can befound in e.g. Kitaigorodsky, A. I. (1973), Molecular Crystals andMolecules, Academic Press, New York; Bunn, C. W. (1948), ChemicalCrystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L.E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York.The analysis gave the diffractogram depicted in FIG. 1. The main peaks,with positions and relative intensities, have been extracted from thediffractogram in FIG. 1 and is given below in table 1. The relativeintensities are less reliable and instead of numerical values thefollowing definitions are used.

% Relative Intensity Definition  25-100 vs (very strong) 10-25 s(strong)  3-10 m (medium) 1-3 w (weak) <1 vw (very weak)

Some additional very weak peaks found in the diffractogram have beenomitted from table 1.

TABLE 1 Positions and intensities of the major peaks in theXRP-diffractogram of the magnesium salt of S-omeprazole trihydrate.d-value / Å Relative Intensity 2.67 m 2.79 m 3.27 m 3.52 s 3.82 s 3.96vs 4.14 m 5.2 m 5.6 m 6.7 vs 6.9 s 8.3 w 16.6 vs

Example 2

S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolepotassium salt

A solution of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole(15.4 g, 46.8 mmol) in toluene (70 ml) was heated to 50° C. and water(0.05 ml, 2,8 mmol) and D-(−)-diethyl tartrate (2.02 g, 9.82 mmol) wereadded. The reaction mixture was stirred for 20 minutes.Titanium(IV)isopropoxide (1.34 g, 4.68 mmol) was added and the reactionmixture was stirred for 45 minutes. The mixture was cooled to 30° C. anddiisopropylethylamine (0.91 g, 7.01 mmol) was added followed by cumenehydroperoxide (9.52 g, 51.89 mmol). The resultant mixture was stirred at30° C. for 3 hours. Methanol (40 ml) was added followed by potassiumhydroxide (3.05 g, 46.8 mmol) in methanol (30 ml). Seed crystals wereadded and the reaction mixture was stirred at 35° C. overnight. Theprecipitated product was filtered off, washed with methanol and tolueneand dried in vacuo. Yield: 9.74 g (54%).

Example 3

S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolepotassium salt

Water (157.6 gl) was added to a solution of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazolein toluene (370 ml; 211.5 g/l) with a water content of 0.031% (w/w),followed by addition of D-(−)-diethyl tartrate (8.55 ml). The solutionwas heated to 50° C. and stirred at this temperature for 20 minutes.Titanium(IV)isopropoxide (7.15 ml) was added and reaction was left at50° C. for 45 minutes. The temperature was lowered to 30° C. anddiisopropylethylamine (6.2 ml) was added. Cumene hydroperoxide was addedat an appropriate speed to maintain the temperature from 28° C. to 34°C. The temperature was raised to 35° C. after 2 hours and potassiummethoxide (24.55 g) in methanol (222 ml) was added. The mixture wasfiltered after 14 hours and the crystals were washed withmethanol:toluene (240 ml; 1:1) and methanol (120 ml) and dried. Yield:79 g (74%), ee>99.9%. [α]_(D) ²⁰=+28.7° (c=1%, water); Assay: 89% isS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolepotassium salt (11% is methanol).

1H-NMR (200 MHz, DMSO-d6, δ ppm): 2.23 (s, 3H), 2.24 (s, 3H), 3.71 (s,3H), 3.75 (s 3H), 4.40 (d, 1H), 4.78 (d, 1H), 6.58 (dd, 1H), 7.00 (d,1H), 7.35 (d, 1H), 8.25 (s, 1H.

The products from Examples 2 and 3 were analysed using X-ray powderdiffraction as described in Example 1 and gave the diffractogramdepicted in FIG. 2 and given below in

Table 2. Some additional very weak peaks found in the diffractogram havebeen omitted from Table 2.

TABLE 2 Positions and intensities of the major peaks in theXRP-diffractogram of the potassium salt of S-omeprazole. Relatived-value/ Relative d-value/Å intensity (Å) intensity 13.6 vs 3.52 m 10.6vw 3.42 w 7.8 m 3.38 w 6.8 m 3.34 m 6.5 m 3.28 w 6.2 w 3.20 m 6.1 m 3.12w 5.8 s 3.06 w 5.4 m 3.03 w 5.3 w 2.97 w α1 = 1.54060 Å 5.2 w 2.93 vw5.0 vw 2.89 w 4.75 m 2.85 m 4.71 w 2.76 w 4.52 w 2.71 vw 4.42 w 2.66 vw4.32 w 2.58 w 4.27 m 2.57 w 3.98 vw 2.56 w 3.92 w 2.52 vw 3.89 w 2.47 vw3.87 w 2.45 vw 3.81 w 2.43 vw 3.74 m 2.40 vw 3.60 m 2.38 vw 3.55 m 2.31vw

Example 4

S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt

Methanol (148 kg) was added toS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolepotassium salt (71 kg, methanol content=13%). MgSO₄×7 H₂O (40 kg) wasadded to the mixture while stirring. After 70 minutes the mixture wasfiltered and the filtrate was washed with methanol (46 kg). The solutionwas concentrated to a volume of 100 liter, acetone (253 kg) was addedand the resulting mixture was left for 4 hours. The precipitated productwas filtered off, washed with acetone and water. The wet crystals wereimmediately used as is described in Example 1.

Example 5

S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt dihydrate

5.0 g of the moist product from Example 4 with an approximate drycontent of 74%, was dried in vacuum at 35° C. over night to yield 3.58 g(2.68 mmol) ofS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt dihydrate, named Form B.

The product was analyzed using X-ray powder diffraction as described inExample 1, and the analyze gave the diffractogram depicted in FIG. 3 andgiven below in Table 3. Some additional peaks with low intensities foundin the diffractogram have been omitted from Table 3.

TABLE 3 Positions and intensities of the major peaks in theXRP-diffractogram of the magnesium salt of S-omeprazole dihydrate, FormB. d-value/Å Relative Intensity 4.19 m 4.45 m 4.68 m 4.79 s 4.91 s 4.98s 5.1 m 5.4 s 5.5 m 5.6 m 5.8 m 6.3 m 6.7 s 7.9 m 8.1 s 11.0 m 11.8 m14.9 vs

Convertion of magnesium salt of S-omeprazole dihydrate to trihydrate

This material was subsequently processed toS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt trihydrate according to the procedure described for themoist substance in Example 1.

Example 6

S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt dihydrate

A methanolic solution ofS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt was prepared as is described in Example 4. Such asolution ofS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt (1.86 g) in 5 ml methanol was concentrated by evaporationuntil 1.58 ml methanol remained. Then, a mixture of 1.6 ml water and6.32 ml aceton was added. The solution was allowed to crystallize during26 h at room temperature. The resulting crystals were filtered off anddried at 40 ° C. under reduced pressure giving 1.17 g ofS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt dihydrate, named form A.

The product was analyzed using X-ray powder diffration as described inExample 1 and gave the diffractogram depicted in FIG. 4 and given belowin Table 4. Some additional peaks with low intensities found in thediffractogram have been omitted from Table 4.

TABLE 4 Positions and intensities of the major peaks in theXRP-diffractogram of the magnesium salt of S-omeprazole dihydrate, FormA. d-value/Å Relative Intensity 3.04 s 3.14 s 3.18 m 4.05 s 4.19 s 4.32m 4.54 s 4.69 vs 5.2 s 5.3 s 5.8 s 6.2 vs 6.6 s 15.5 vs

Example 7

S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt trihydrate

22,0 g (29,1 mmol) ofS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolepotassium salt was dissolved in 40 mL of water. The solution was seededwith 0,11 g (0,1 mmol)S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt trihydrate. 22 mL (69,6 mmol) of MgSO₄ (aq) was addedunder a 3 h period. The slurry was filtered off and the precipitate waselutriated in water for approximately 30 minutes and the crystals werefiltered off and dried (35° C., vacuum).

Yield: 9,15 g (11,6 mmol; 80%). The substance had a purity (HPLC):99,8area %, Mg content: 3,40% (w/w) and ee: 99,8%.

The product was analyzed using X-ray powder diffraction and the resultcomplies with s FIG. 1 and Table 1.

Reference Example A

S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolemagnesium salt

(The method used is in accordance with the method described in Example Ain WO 96/01623)

Magnesium (0.11 g, 4.5 mmol) was dissolved and reacted with methanol (50ml) at 40° C. with a catalytic amount of methylene chloride. Thereaction was run under nitrogen and was finished after five hours. Atroom temperature a mixture of the two enantiomers [90%(−)-isomer and10%(+)-isomer] of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(2.84 g, 8.2 mmol) was added to the magnesium methoxide solution. Themixture was stirred for 12 hours whereupon a small amount of water (0.1ml) was added in order to precipitate inorganic magnesium salts. After30 minutes stirring, these inorganic salts were filtered off and thesolution was concentrated on a rotavapor. The residue was now aconcentrated methanolic solution of the enantiomeric mixture (i.e. thetitle compound contaminated with the (+)-isomer), with an optical purity(enantiomeric excess, e.e.) of 80%. This mixture was diluted withacetone (100 ml) and after stirring at room temperature for 15 minutes,a white precipitate was obtained. Additional stirring for 15 minutes andthereafter filtration afforded 1.3 g (50%) of the title compound aswhite crystals. Chiral analyses of the crystals and mother liquor wereperformed by chromatography on an analytical chiral column. The opticalpurity of the crystals and mother liquor was found to be 98.4 e.e. and64.4% e.e., respectively. Thus, the optical purity (ee.) has beenenhanced from 80% to 98.4% simply by crystallizing the Mg-salt from amixture of acetone and methanol. The product was crystalline as shown bypowder X-ray diffraction and the magnesium content was 3.44% as shown byatomic absorption spectroscopy. [α]_(D) ²⁰=−131.5° (c=0.5%, methanol).

The product was analyzed using X-ray powder diffraction as described inExample 1 and gave the diffractogram depicted in FIG. 5 and given belowin Table 5. Some additional very weak peaks found in the diffractogramshave been omitted from Table 5.

TABLE 5 Positions and intensities of the major peaks in theXRP-diffractogram shown in FIG. 5. d-value/Å Relative Intensity 2.90 s3.41 s 3.90 s 4.13 s 4.79 vs 5.00 vs 5.4 vs 5.7 s 6.3 s 6.8 s 7.8 s 8.4vs 10.8 s 12.2 s 15.1 vs

What is claimed is:
 1. The magnesium salt of S-omeprazole trihydrate,wherein the compound is characterized by the following major peaks inits X-ray diffractogram: d-value / Å Relative Intensity 2.67 m 2.79 m3.27 m 3.52 s 3.82 s 3.96 vs 4.14 m 5.2 m 5.6 m 6.7 vs 6.9 s 8.3 w 16.6vs


2. The magnesium salt of S-omeprazole trihydrate according to claim 1,wherein the compound is in a highly crystalline form.
 3. The magnesiumsalt of S-omeprazole trihydrate according to claim 1, wherein thecompound is in a stable form.
 4. A process for the preparation of themagnesium salt of S-omeprazole trihydrate according to any of claims 1,2 or 3 which comprises treating a magnesium salt of S-omeprazole anyother form with water.
 5. A process for the preparation of the magnesiumsalt of S-omeprazole trihydrate according to any of claims 1, 2 or 3which comprises the following steps: a) mixing a potassium salt ofS-omeprazole with an organic solvent; b) converting the potassium saltof S-omeprazole into a corresponding magnesium salt of S-omeprazole bytreating the potassium salt with a magnesium source; c) precipitatingthe magnesium salt of S-omeprazole by addition of a non-solvent; d)isolating the obtained magnesium salt of S-omeprazole; e) treating theobtained magnesium salt of S-omeprazole with water, and f) isolating anddrying the obtained magnesium salt of S-omeprazole trihydrate.
 6. Theprocess according to claim 5, wherein the organic solvent of step a) ismethanol.
 7. The process according to claim 5, wherein the non-solventof step c) is acetone.
 8. The process according to claim 5 wherein stepsa) to e) are replaced by the following single step: converting thepotassium salt of S-omeprazole into a corresponding magnesium salt ofS-omeprazole by treating the potassium salt with a magnesium source inwater.
 9. The process according to claim 5, wherein the magnesium sourceis magnesium sulfate.
 10. The process according to claim 8, wherein themagnesium source is magnesium sulfate.
 11. A pharmaceutical compositioncomprising the magnesium salt of S-omeprazole trihydrate according toany of claims 1, 2 or 3 as active ingredient and a pharmaceuticallyacceptable carrier.
 12. A method of treating a gastric acid relatedcondition which method comprises administering to a subject sufferingfrom said condition a therapeutically effective amount of the magnesiumsalt of S-omeprazole trihydrate according to any of claims 1, 2 or 3.